It is clear that the progress of diabetes research during the coming decade will depend heavily upon the ability to utilize the mouse as an experimental model to investigate both basic and clinically relevant questions in diabetes research. The Transgenic and Knock-out Mouse Core (TKMC, Core A) provides investigators at UCLA, UCSD, the Salk Institute, and Cedars-Sinai with a wide array of genetic manipulations in the mouse including transgenic genes, homologous recombination in embryonic stem cells (ES cells), creation of chimeric mice from ES cells, and the most cutting-edge approaches to performing reverse genetics in the mouse. Transgenic, knock-out and knock-in mouse models are created that utilize the most advanced approaches including conditional Tet-inducible and tamoxifen-inducible transgenes, tissue-specific and conditional knock-outs using Cre-LoxP and Flp recombinases and recombination-mediated cassette exchange (RMCE), BAC transgenics, BAC-Trap, RiboTag, and other specialized technologies. This Core is an outstanding example of how extraordinarily specialized techniques, highly trained dedicated personnel, specially constructed facilities, and expensive equipment can be accessed by researchers who could not reasonably expect to develop them on an individual basis. Key objectives are: 1. To create innovative and important mouse models for studies of diabetes and its complications 2. To eliminate barriers to the most cutting-edge mouse genetic approaches for the DERC membership 3. To provide outstanding, reliable, and high quality mouse embryology and genetic services 4. To advance the technology of genetic manipulation of the mouse genome The availability of this Transgenic and Knock-out Mouse Core in coordination with the Metabolic and Molecular Physiology Core, the Genomics and Epigenetic Core, and the Novel Target identification and Assay Development Core, will enable our members to conduct versatile, cutting-edge, reverse genetic research in the mouse with a battery of multidisciplinary, state-of-the-art techniques.